Drugs are conventionally administered orally or via injection, often at a site remote from the target. Over a relatively short period of time, the drug diffuses into the circulation system of the patient and is distributed to the various organs and tissues, at least one of which is the intended target for the drug. The action of the drug on organs other than the target may result in undesirable side effects. Finally, the drug is metabolized or otherwise irreversibly removed from the organism by excretion or chemical deactivation. When drugs are delivered orally or by injection, the level and duration of availability of the drug cannot be controlled independently; only the size and frequency of the dose can be manipulated. Typically, there is an initially high concentration of available drug at the site of injection or in the circulatory system which then decreases gradually as the drug is distributed and consumed within the body of the patient.
In controlled, sustained delivery, a formulation of drug and a carrier is administered to the patient by injection or implantation. The carrier forms a drug reservoir that protects the stored drug from extraneous removal mechanisms and releases the drug to the biological reservoir at a predetermined rate. Controlled, sustained delivery of a drug prevents undesirable peaking of blood levels and makes the drug available at an optimum and uniform concentration over an extended period of time. Only the released drug is subject to removal via metabolism and excretion. In the controlled, sustained delivery method, there is potential for control of the drug release rate by factors inherent in the delivery package itself. Some of these inherent factors, such as the rate of hydrolysis of an absorbable polymer, or the rate of transdermal diffusion, are in contrast to the externalized controls associated with classical delivery methods, e.g., rate of tablet intake, frequency of injections, etc. In accordance with prior methods, the maintenance of therapeutic blood levels of an antibiotic, for example, requires a fairly precise dosing of tablets. Though this may be uncomplicated for many adults, it may be difficult where gastric problems are present or for infants, the very infirm, or in veterinary work, such as with range animals.
The present invention provides a device that may be implanted on a one-time basis and which releases and maintains reasonably effective and predictable drug levels, thus eliminating the need for continual external supervision. Known methods for controlled release of drugs include the anthelmintic bolus based on an absorbable polymer. Another method which has been commercialized is the transdermal delivery of life-maintaining drugs such as nitroglycerine.
The present invention relates to the system wherein a controlled-release drug system/package is placed in or close to the target area. A great advantage of this system is that the medication does not have to traverse needless miles of the vascular system, become diluted and inactivated in countless organs and tissues, all of which may lead to undesirable side effects, and all of which is usually compensated for by overdosing, thus even further accentuating undesirable side effects.
The present invention provides a localized device/system which delivers effective doses of a drug, such as an antibiotic, directly to the affected target area, in which the matrix or releasing medium is completely absorbable. An example thereof are the gums in cases of periodontal diseases.
The present device may be dispensed in the shape of a pellet. In addition, several medications may be combined in one pellet, for example, an antibacterial (or an antibiotic combined with a non-antibiotic medication), combined with an anti-inflammatory agent, a corticosteroid and a pain killer such as benzocaine, thus preventing complete therapy to the infected area.
The compositions of the present invention possess a putty-like consistency at room and body temperatures and thus may be easily and conveniently shaped by hand, into the form most desirable for placement in a pocket in the body from which sustained release of a medicament is desirable (such as the naturally formed pocket between the base of a tooth and the adjoining tissues, when the composition is used in connection with periodontal disease). In addition to this moldability by hand, these compositions also additionally conform to body or tissue or organ contours by yielding to gentle pressures in the implant area without becoming runny, or losing their consistency. Prior art sustained release compositions do not possess a putty-like consistency at room and body temperatures and thus lack the above-described advantages of the composition of the present invention.
A very unique characteristic of this type of consistency and rheology lies in its response to elevated temperatures. Thus, while some compositions (either pure compounds, or polymers or waxes, for example) remain solids up to the melting/softening temperature, and soften or melt above this temperature, the present matrix shows only a barely perceptible softening upon heating. Thus, for example, while the polyalkene oxalates of Shalaby, et al. in U.S. Pat. No. 4,186,189, are either rigid solids (non-conformable, irritating as implants) below the melting point, or runny liquids above the melting temperature (and thus will flow away from the target area into unwanted tissues and organs) the present matrix will maintain its moldable, conformable consistency over a very wide range of temperatures.
A preferred composition of the present invention includes a matrix consisting of calcium stearate, dextran and castor oil. The consistency of this composition may be easily altered merely by increasing the castor oil content and, indeed, this adjustment allows the composition to be pushed through a standard dental syringe with little effort. As has been shown experimentally, the consistency can also be varied without altering the ratio of components. If the matrix is prepared as a composition, the consistency of which is adequate for bone hemostasis, it can be made considerably more rigid by passing it through a 3-roll mill. The resulting material which has not been altered chemically, may now be ideal for packing around infected gums by means of a spatula. The calcium stearate, dextran and castor oil compositions containing varying concentrations of meclocycline sulfosalicylate were evaluated in vitro for release rate characteristics. Release rates of the antibiotic in buffer were monitored at several temperatures and were found to be extremely regular, predictable and at therapeutic levels. These compositions, containing the meclocycline sulfosalicylate, thus possess excellent release rates, easily adjustable consistency and, in addition, the absorption rates of the entire composites may be controlled via adjustment of the dextran content. This composition can furthermore be prepared without need for degradative and stressful conditions (such as temperature, time, catalysts, etc.). All of these features provide an excellent medium or matrix for controlled drug release. In contrast, the prior art sustained-release compositions do not possess the above-described advantages.
Certain of the compositions of the present invention also constitute absorbable bone waxes so that when an antibiotic is incorporated therein, the compositions, when used in the conventional manner as bone waxes, are provided with antimicrobial activity. This helps prevent infection of the bone marrow which is of concern in the field of orthopedics where shattered limbs may be infected before the surgeon operates.
The present composition is also advantageous in the field of immunology. During the normal injection of an antigen (killed viruses, synthetic polypeptides, etc.) dispersed in saline solution, for example, the contents of the injection may course through the entire body within the span of an hour or two. This leads to a "flash" effect, a peak reaction (fever, rashes, etc.) and is generally of short duration which requires periodic booster shots. If the same antigen were to be incorporated in the matrix of the present invention and extruded as a filament under the skin (using a dental syringe, for example) the antigen would be released at a rate that is controllable in the same manner as the other applications described herein. This predictable, controllable, uniform rate, would release levels of antigen conducive to the most effective build-up of antibody, and in its sustained action would avoid peak/flash side effects as well as the need for booster shots.
In accordance with the present invention, the pharmacologically active agent may be an anti-cancer drug such as a chemotherapeutic agent or a radioacitve isotope such as iodine 125. The composition incorporating an anti-cancer agent could be extruded as a rod right into the affected sites or pellets could be implanted in or near the affected area. Shapes of special design or consistency may also be implanted.
In accordance with one embodiment of the present invention, the pharmacologically active agent may consist of magnetic particles which are blended into the absorbable putty-like composition which is then implanted in the body and used in connection with hyperthermia therapy.
In accordance with a further embodiment of the present invention, when used as an anti-cancer composition, natural iodine is incorporated into the absorbable putty-like matrix and stored as such. Thereafter, just prior to use, the iodine is converted to a radioactive isotope by exposure in an atomic pile. With respect to such use, it must be ensured that other radioactive species, which may be generated, are not too long-lived or toxic.